Concert Pharmaceuticals and GlaxoSmithKline recently announced a collaboration to develop deuterium-containing medicines, including CTP-518, a partially deuterated version of the HIV protease inhibitor, atazanavir (Reyataz™), marketed by Bristol-Myers Squibb. Reyataz™ is used in combination therapy to treat HIV/AIDS and, for most patients, the recommended dose is one 300mg tablet daily taken with ritonavir (Norvir™). Ritonavir was originally developed as a ‘stand-alone’ HIV protease inhibitor but is now primarily used, not for its antiviral activity, but to ‘boost’ levels of other protease inhibitors by inhibiting their metabolism. Despite its marked benefits as part of combination therapy, ritonavir is poorly tolerated by some patients and also influences the metabolism of concurrently administered drugs, especially those metabolised by CYP 3A4.
Concert is pioneering the modification of existing medicines by selectively replacing hydrogen atoms with deuterium atoms in the expectation that the modified compounds will have similar activity at the target enzyme or receptor, together with improved ADME properties. CTP-518 has been shown to have similar antiviral potency to atazanavir but slower hepatic metabolism, leading to the hope that it could be used clinically without the need for ‘boosting’ by ritonavir. This could lead to better safety and tolerability for patients and also allow for the inclusion of CTP-518 in fixed dose regimens. CTP-518 is expected to enter Phase I clinical trials in the second half of 2009.
Concert has filed a patent application (WO20081566632) claiming derivatives of atazanavir, including compounds 120 and 122.
The antiviral activities of compounds 120 and 122 were shown to be similar to, or slightly better than, that of atazanavir, both in the presence and absence of serum proteins. In human liver microsomes, compounds 120 and 122 showed an approximately 50% increase in half life compared with atazanavir. Following oral co-dosing in rats, compound 122 showed a 43% increase in half life, a 67% increase in Cmax and an 81% increase in AUC compared with atazanavir. When administered to chimps, both compounds showed around 50% increases in half life compared with atazanavir and about 2-fold increases in urine concentration.
Thanks for follow up. I thought carbamates were generally fairly metabolically stable and that these t-butyls would be relatively inert sites so the observations of differences don’t “fit” expectations. Metabolism can be complicated and surprising in my (limited) experience yet my first targets would be the pyridine ring (with mono and di-hdroxylation as possibilities here?) or the hydroxyl group then maybe the amide (although much steric hindrance with both) but how the D-switch would effect those pathways is not along direct lines. Could there be some intramolecular assistance or a slight change in conformational states that plays a role? Presumably if that detailed work has not already been done might anticipate would have to conduct a thorough investigation for Submissions and hope would get published one day.
Not knowing (or searching for) the metabolism of atazanavir is the noted difference due the the differences in the hydrolysis of the carbamates or due to t-butyl D-atoms?
CMCguy,
As far as we’re aware no detail has been published on the metabolism of the deuterated compound(s). The major metabolites of atazanavir appear to be mono- and di-hydroxylated species. Hydrolysis of atazanavir is reported to be a minor metabolic pathway.